Abstract
Although the antiviral effects of amantadine sulphate (1‐aminoadamantan sulphate) have not been characterized for the hepatitis C virus (HCV), previous pilot studies have suggested promising results in patients with chronic hepatitis C. The aim of the present study was to compare the efficacy, safety, and health‐related quality of life (HRQOL) of interferon alfa (IFN‐α) alone or in combination with oral amantadine for treatment of chronic hepatitis C. One hundred nineteen previously untreated patients with chronic hepatitis C were randomly allocated to treatment with IFN‐α2a at a dose of 6 megaunits 3 times a week subcutaneously for 24 weeks, followed by 3 megaunits thrice weekly for an additional 24 weeks plus amantadine sulphate administered orally 100 mg twice a day for 48 weeks or the same IFN regimen plus a matched placebo. The primary endpoint was undectable serum HCV RNA (<1,000 copies/mL) at week 24 after treatment. At the end of treatment and the 24‐week follow‐up period serum HCV RNA was undetectable in 20 (34%) and 6 (10%) of the 59 patients treated with the combination IFN‐α plus amantadine and in 20 (33%) and 13 (22%) of the 60 patients treated with IFN‐α alone, respectively (P = n.s.). Discontinuation of therapy for adverse events was similar in both treatment groups. Although treatment with IFN‐α worsened HRQOL, combination with amantadine showed a substantial trend to improve fatigue and vigor. In conclusion, combination therapy IFN‐α plus amantadine is as effective as IFN‐α monotherapy in previously untreated patients with chronic hepatitis C.
REFERENCES
- 1. van der Poel CL, Cuypers HT, Reesink HW. Hepatitis C virus six years on. Lancet 1994; 344:1475–1479.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=m7968123&dopt=Citation [DOI] [PubMed] [Google Scholar]
- 2. Poynard T, Leroy V, Cohard M, Thevenot T, Mathurin P, Opolon P, Zarski JP. Meta‐analysis of interferon randomized trials in the treatment of viral hepatitis C: effects of dose and duration. Hepatology 1996; 24:778–789.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=m8855176&dopt=Citation [DOI] [PubMed] [Google Scholar]
- 3. Lindsay KL. Therapy of hepatitis C: overview. Hepatology 1997; 26 (Suppl 1):71–77. [DOI] [PubMed] [Google Scholar]
- 4. Poynard T, Marcellin P, Lee S, Niederau C, Minuk GS, Ideo G, Bain V, et al. for the International Hepatitis Interventional Therapy Group (IHIT). Randomised trial of interferon α2b plus ribavirin for 48 weeks or for 24 weeks versus interferon α2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 1998; 352:1426–1432.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=m9807989&dopt=Citation [DOI] [PubMed] [Google Scholar]
- 5. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et al. for the Hepatitis Interventional Therapy Group (HIT). Interferon alfa‐2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998; 339:1485–1492.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=m9819446&dopt=Citation [DOI] [PubMed] [Google Scholar]
- 6. Oxford JS, Schild GC. In vitro inhibition of rubella virus by 1‐adamantanamine hydrochloride. Arch Gesamte Virusforsch 1965; 17:313–329.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=m5882880&dopt=Citation [DOI] [PubMed] [Google Scholar]
- 7. Kato N, Eggers HJ. Inhibition of uncoating of fowl plague virus by l‐adamantanamine hydrochloride. Virology 1969; 37:632–641.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=m5781863&dopt=Citation [DOI] [PubMed] [Google Scholar]
- 8. Pfau CJ, Trowbridge RS, Welsh RM, Staneck LD, O'Connell CM. Arenaviruses: inhibition by amantadine hydrochloride. J Gen Virol 1972; 14:209–211.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=m4622136&dopt=Citation [DOI] [PubMed] [Google Scholar]
- 9. Koff WC, Elm JL, Halstead SB. Inhibition of dengue virus replication by amantadine hydrochloride. Antimicrob Agents Chemother 1980; 18:125–129.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=m7416739&dopt=Citation [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Leibowitz JL, Reneker SJ. The effect of amantadine on mouse hepatitis virus replication. Adv Exp Med Biol 1993; 342:117–122.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=m8209717&dopt=Citation [DOI] [PubMed] [Google Scholar]
- 11. Dolin R, Reichman RC, Madore HP, Maynard R, Linton PN, Webber‐Jones J. A controlled trial of amantadine and rimantadine in the prophylaxis of influenza A infection. N Engl J Med 1982; 307:580–584.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=m7050702&dopt=Citation [DOI] [PubMed] [Google Scholar]
- 12. Hay AJ, Wolstenholme AJ, Skehel JJ, Smith MH. The molecular basis of the specific anti‐influenza action of amantadine. EMBO J 1985; 4:3021–3024.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=m4065098&dopt=Citation [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Wang C, Takeuchi K, Pinto LH, Lamb RA. Ion channel activity of influenza A virus M2 protein: characterization of the amantadine block. J Virol 1993; 67:5585–5594.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=m7688826&dopt=Citation [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Smith JP. Treatment of chronic hepatitis C with amantadine. Dig Dis Sci 1997; 42:1681–1687.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=m9286234&dopt=Citation [DOI] [PubMed] [Google Scholar]
- 15. Younossi ZM, Perrillo RP. The roles of amantadine, rimantadine, ursodeoxycholic acid, and NSAIDs, alone or in combination with alpha interferons, in the treatment of chronic hepatitis C. Semin Liver Dis 1999; 19 (Suppl 1):95–102.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=m10349697&dopt=Citation [PubMed] [Google Scholar]
- 16. Tabone M, Ercole E, Zaffino C, Sallio Bruno F, Pera A, Bonino F. Amantadine hydrochloride decreases serum ALT activity without effects on serum HCV‐RNA in chronic hepatitis C patients. Ital J Gastroenterol Hepatol 1998; 30:611–613.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=m10076783&dopt=Citation [PubMed] [Google Scholar]
- 17. Caronia S, Crossey M, Murray‐Lyon I, Lypsnyi D, Main J, Thomas HC, Foster G. A pilot study of interferon plus amantadine versus interferon alone in the treatment of chronic hepatitis C [Abstract]. J Hepatol 1999; 30 (Suppl 1):138. [Google Scholar]
- 18. Zeuzem S, Rüster B, Roth WK. Clinical evaluation of a new polymerase chain reaction assay (Amplicor™ HCV) for detection of hepatitis C virus. Z Gastroenterol 1994; 32:342–347.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=m7526563&dopt=Citation [PubMed] [Google Scholar]
- 19. Lee J‐H, Roth WK, Zeuzem S. Evaluation and comparison of different hepatitis C virus genotyping and serotyping assays. J Hepatol 1997; 26:1001–1009.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=m9186830&dopt=Citation [DOI] [PubMed] [Google Scholar]
- 20. McNair DM, Lorr M, Droppleman LF. Profile of Mood States. San Diego: Educational and Industrial Testing Service; 1971. [Google Scholar]
- 21. Bullinger M, Heinisch M, Ludwig M, Geier S. Skalen zur Erfassung des Wohlbefindens: Psychometrische Analysen zum “Profile of Mood States” (POMS) und zum “Psychological General Wellbeing Index” (PGWI). Zeitschrift für Differentielle und Diagnostische Psychologie 1990; 11:53–61. [Google Scholar]
- 22. Gandek B, Ware JE. SF‐36 Health Survey Manual and Interpretation Guide. Boston: New England Medical Center, The Health Institute; 1993;. [Google Scholar]
- 23. Bullinger M, Kirchberger I, von Steinbüchel N. Der Fragebogen Alltagsleben—ein Verfahren zur Erfassung der gesundheitsbezogenen Lebensqualität. Zeitschrift für Medizinische Psychologie 1993; 2:121–131. [Google Scholar]
- 24. Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 1994; 19:1513–1520.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=m8188183&dopt=Citation [PubMed] [Google Scholar]
- 25. Skehel JJ. Amantadine blocks the channel. Nature 1992; 358:110–111.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=m1377366&dopt=Citation [DOI] [PubMed] [Google Scholar]
- 26. Martin J, Navas S, Fernandez M, Rico M, Pardo M, Quiroga JA, Zahm F, et al. In vitro effect of amantadine and interferon alpha‐2a on hepatitis C virus markers in cultured peripheral blood mononuclear cells from hepatitis C virus‐infected patients. Antiviral Res 1999; 42:59–70.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=m10333143&dopt=Citation [DOI] [PubMed] [Google Scholar]
- 27. Fong TL, Fried MW, Clarke‐Platt J. A pilot study of rimantadine for patients with chronic hepatitis C unresponsive to interferon therapy. Am J Gastroenterol 1999; 94:990–993.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=m10201471&dopt=Citation [DOI] [PubMed] [Google Scholar]
- 28. Krupp LB, Coyle PK, Doscher C, Miller A, Cross AH, Jandorf L, Halper J, et al. Fatigue therapy in multiple sclerosis: results of a double‐blind, randomized, parallel trial of amantadine, pemoline, and placebo. Neurology 1995; 45:1956–1961.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=m7501140&dopt=Citation [DOI] [PubMed] [Google Scholar]
- 29. Brillanti S, Foli M, Di Tomaso M, Gramantieri L, Masci C, Bolondi L. Pilot study of triple antiviral therapy for chronic hepatitis C in interferon alpha non‐responders. Ital J Gastroenterol Hepatol 1999; 31:130–134.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=m10363198&dopt=Citation [PubMed] [Google Scholar]
- 30. Brillanti S, Levantesi F, Foli M, Di Tomaso M, Bolondi L. Amantadine and Rebetron™ exert a synergistic antiviral effect on HCV replication in interferon‐α non‐responders with chronic hepatitis C [Abstract]. Gastroenterology 1999; 116 (Suppl 1):212. [Google Scholar]